The objective of this project is the identification of molecular targets for the development of novel mechanism-based therapies for the prevention and treatment of Kaposi's sarcoma (KS). KS is a neovascular tumor that typically affects the skin, oral mucosa, and visceral organs. It is the most frequent cancer arising in HIV-infected individuals and is an AIDS-defining illness by CDC guidelines. Unfortunately, clinical management of this tumor has proven to be challenging. Today, despite extensive investigation into its molecular etiology, KS remains an incurable disease. The recent identification of the KS-associated herpesvirus (KSHV) as the viral etiological agent for KS presents a unique opportunity to develop pathogenesis-based treatments for this neoplasm. Identification of the gene(s) necessary for KSHV tumorigenesis, and the nature of the molecular events mediating their oncogenic potential, is an essential first step for the successful development of such therapies. In this regard, we have previously shown that only one candidate KSHV oncogene, vGPCR, is able to induce KS-like tumors when specifically expressed in the vascular endothelium of mice. We further found that expression of vGPCR was confined to only a few cells yet was necessary for KS maintenance through a paracrine mechanism. In this research proposal, we hypothesize that the paracrine secretions elaborated by vGPCR-expressingcells represent novel molecular targets for the prevention and treatment of KS. We will accomplish the following specific aims: 1. examine the role of vGPCR paracrine secretions in Kaposi's sarcomagenesis; 2. identify the Akt effectors which promote the survival of vGPCR-expressingcells; and 3. examine the role of the Akt/TSC/mTOR pathway in paracrine neoplasia.These studies will provide fundamental insight(s) into the molecular mechanisms involved in the development and maintenance of Kaposi's sarcoma and will further expose critical molecular targets for the development of pathogenesis-based therapies for the prevention and treatment of this disease.